Lymphohematopoietic chimerism was first shown to be associated with donor-specific allograft tolerance more than 60 years ago. However, early clinical experience with bone marrow transplantation soon revealed that conventional, myeloablative approaches were far too toxic and the risk of graft-versus-host disease too great to justify using this technology for the purpose of organ allograft tolerance induction in the absence of malignant disease. In this review, we discuss a step-wise approach that has been applied by several centers to establish less toxic approaches to using hematopoietic cell transplantation (HCT) for tolerance induction. These steps include (i) feasibility and efficacy data for tolerance induction in large animal models; (ii) safety data in clinical trials for patients with hematologic malignancies; and (iii) pilot trials of combined HCT and kidney transplantation for tolerance induction. Thus far, only one published trial conducted at the Massachusetts General Hospital in Boston has achieved long-term acceptance of human leukocyte antigen-mismatched kidney allografts without chronic immunosuppressive therapy. Alternative protocols have been successful in large animals, but long-term organ allograft tolerance has not been reported in patients. Thus, proof-of-principle that nonmyeloablative induction of mixed chimerism can be used intentionally to induce organ allograft tolerance has now been achieved. Directions for further research to make this approach applicable for a broader patient population are discussed.